The goal of the Program Project is to identify genetic variations that interact with the environment to affect the expression and clustering of psychosocial and biobehavioral endophenotypes that increase cardiovascular disease (CVD). Exaggerated stress reactivity is likely to be an important CVD endophenotype. Evidence suggests that exaggerated reactivity is associated with increased CVD, and evidence suggests it has a genetic basis. Ambulatory measures of reactivity provide a crucial complement to laboratory studies because they demonstrate the ecological validity of the relationship of hostility and exaggerated reactivity in the environment where pathogenesis occurs. Project 3 will provide measurements of ambulatory stress reactivity for each of a sample of 400 probands (half African American and half Caucasian, half men and half women, and half scoring in the top and half in the bottom 20% on a valid, measure of hostility that predicts CVD and has heritability estimates of 40-55%) and at least one sibling for every proband, to make a total sample of 800-1200 subjects who will participate in the protocol of this project. These measurements will include blood pressure and heart rate variability, catecholamine and cortisol reactivity, and subjective stress and negative mood collected during a 24-hour period of normal daily activities in the natural environment. Both total variability and variability directly attributable to perceived stress and to negative mood will be available for cardiovascular measures, through the use of novel techniques of regression analysis. Neurohumoral activity will be determined by assay of urinary levels in daytime and overnight samples. Personal digital assistants (PDAs) will be used to collect subjective ratings during ambulatory monitoring. Our first goal will be to evaluate a minimum of 41 candidate genes/loci that act directly, in interaction with environmental factors, as a function of linkage disequilibrium with other sites, or membership in haplotypes, to influence hostility and ambulatory cardiovascular & neuroendocrine function. Collected ambulatory data will be combined with data from other Projects to determine genes/loci that affect the clustering of exaggerated ambulatory stress reactivity with hostility and other psychosocial and biobehavioral endophenotypes for CVD. In collaboration with the other Projects, Project 3 will advance our understanding of the genetic influences and gene/environment interactions that account for one of the most important CVD risk factors, hostility. The Projects will also explore how SES, sex and ethnicity may moderate the expression of involved genes. Program Project research activities will provide a comprehensive view of the clustering of CVD risk factors across multiple psychosocial and biobehavioral domains, which should lead to a clear understanding of the determinants of CVD and their genetic basis.